Yeast 'DNA damage sensor' provides chemotherapy resistance clue

Cancer Research UK scientists have been part of an international collaboration
that has revealed the structure of a protein found in simple yeast cells and
shown how it flags up damaged DNA for repair. The results of their study are
published in Nature. The finding may provide clues
as to how some cancer cells become resistant to certain chemotherapy drugs.

Researchers based at Cancer Research UK's Paterson Institute for Cancer Research
at the University of Manchester, worked with other US and UK collaborators to
investigate a recently discovered DNA 'damage sensing' protein family. The collaboration
used a technique called X-ray crystallography to show in yeast cells how the
family called alkyltransferase-like proteins (ATLs) – originally discovered
by Paterson scientists– can detect the DNA damage caused by some anti-cancer
drugs, and alert the cell’s DNA repair machinery.

They also found ATLs in organisms as diverse as sea anemones and microscopic
organisms – so it's likely that a similar protein plays the same kind
of 'damage sensor' role in humans.

Some anti-cancer drugs kill tumour cells by damaging their DNA. But sometimes
the treatment fails because tumour cells can repair this DNA damage –
and reverse the effects of the drug.

This latest study suggests that that ATL proteins might contribute to this
drug resistance. Their new work shows how the yeast ATL protein binds to DNA
and 'flips' out the damaged DNA bases, flagging them up for repair.

The scientists already knew that the ATL in yeast cells protect them from being
destroyed by the kind of damage caused by anticancer agents. When the gene for
the ATL protein was deactivated in yeast cells, the yeast cells became very
sensitive to these drugs.

The study of the DNA repair processes in cells is an area of intense activity.
A better understanding of them will help scientists find ways to block DNA repair
which could lead to the development of more effective cancer treatments. A number
of clinical trials based on this concept are being carried out at the moment.

"We have found out how this family of proteins can begin the repair
of certain types of DNA damage.

Now the hunt is on to see if similar processes exist in humans. If so,
they may tell us why some tumours do not respond to certain chemotherapy drugs
and they will provide important new targets for future drug development."

"Our research over several decades has contributed to our understanding
of repair kits in cells and these latest results are an exciting step forward.
Many chemotherapy drugs work by damaging the DNA in cancer cells which destroys
them. But cells can be incredibly resilient and fight back to repair their
damage.

This research reveals for the first time exactly how a key repair protein
can detect the damage caused by some types of chemotherapy and initiate the
DNA repair process. If this process occurs in humans, this may provide new
leads for treating cancer."

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